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The DSpace digital repository system captures, stores, indexes, preserves, and distributes digital research material.Sun, 02 Aug 2015 22:36:23 GMT2015-08-02T22:36:23ZThe cyclooxygenase-2/prostaglandin E2 pathway is involved in the somatostatin-induced decrease of epileptiform bursting in the mouse hippocampushttp://hdl.handle.net/2067/1486
Title: The cyclooxygenase-2/prostaglandin E2 pathway is involved in the somatostatin-induced decrease of epileptiform bursting in the mouse hippocampus
Authors: Ristori, Chiara; Cammalleri, Maurizio; Martini, Davide; Pavan, Barbara; Casini, Giovanni; Cervia, Davide; Bagnoli, Paola
Abstract: The neuromodulatory peptide somatostatin-14 (SRIF) plays an important inhibitory role in epilepsy, but little is known on the signalling mechanisms coupled to this effect of SRIF. We have previously demonstrated that SRIF induces reduction of epileptiform bursting in a model of interictal-like activity in mouse hippocampal slices. In this same model, we investigated whether the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway is part of those signalling mechanisms mediating SRIF anti-epileptic actions. Both the expression of COX-2 (mRNA and protein) and the endogenous release of PGE2 increased in concomitance with epileptiform bursting. In particular, COX-2 protein increased in CA1/CA3 pyramidal layer and in the granular layer of the dentate gyrus. In addition, the selective inhibition of COX-2 by NS-398 markedly decreased endogenous PGE2 release induced by epileptiform bursting and the epileptiform bursting itself. Similar effects on epileptiform bursting were obtained with another COX-2 inhibitor, i.e., meloxicam. SRIF application counteracted the increase of both COX-2 expression and PGE2 release which occurred in concomitance with epileptiform bursting. Interestingly, SRIF and NS-398 comparably reduced epileptiform bursting in a non-additive manner and PGE2 abolished the inhibitory effect of SRIF on epileptiform bursting. These results demonstrate that: i) the COX-2/PGE2 pathway facilitates epileptiform bursting; and ii) SRIF exerts an anti-epileptic role by coupling to the COX-2/PGE2 pathway. In conclusion, we have identified a key set of signalling events that underlie anti-convulsant effects of SRIF in a mouse model of hippocampal bursting, thus providing useful data not only to identify alternative intervention points for the modulation of SRIF function, but also to exploit new chemical space for drug-like molecules.
Description: L'articolo è disponibile sul sito dell'editore http://www.sciencedirect.com/Mon, 31 Dec 2007 23:00:00 GMThttp://hdl.handle.net/2067/14862007-12-31T23:00:00ZAntiangiogenic role of somatostatin receptor 2 in a model of hypoxia-induced neovascularization in the retina: Results from transgenic micehttp://hdl.handle.net/2067/1483
Title: Antiangiogenic role of somatostatin receptor 2 in a model of hypoxia-induced neovascularization in the retina: Results from transgenic mice
Authors: Dal Monte, Massimo; Cammalleri, Maurizio; Martini, Davide; Casini, Giovanni; Bagnoli, Paola
Abstract: PURPOSE. To determine whether the somatostatin receptor 2 (sst2) influences angiogenesis and its associated factors in a model of hypoxia-induced retinal neovascularization.
METHODS. sst1-knockout (KO) mice, in which sst2 is overexpressed and overfunctional, and sst2-KO mice were used. Angiogenesis was evaluated in fluorescein-perfused retinas. Angiogenesis- associated factors were determined by RT-PCR and immunohistochemistry.
RESULTS. Retinal neovascularization was increased in sst2-KO mice, but remained unchanged in sst1-KO compared with wild-type (WT) mice. Retinal levels of sst2 mRNA were not affected by hypoxia. Normoxic levels of angiogenesis regulators were similar in WT and KO retinas except for mRNA levels of IGF-1, Ang-2, and its receptor Tie-2. In WT, hypoxia induced an increase in mRNA levels of (1) VEGF and its receptors, (2) IGF-1R, and (3) Ang-2 and Tie-2. The increase in VEGF and IGF-1R mRNAs was more pronounced after sst2 loss, but was less pronounced when sst2 was overexpressed. In addition, in hypoxic retinas, sst2 loss increased IGF-1 mRNA, whereas it decreased Ang-1, Tie-1, and Tie-2 mRNA levels. Moreover, Tie-1 mRNA increased when sst2 was overexpressed. Immunohistochemistry confirmed the results in hypoxic retinas on increased expression of VEGF, IGF-1, and their receptors after sst2 loss. It also allowed the localization of these factors to specific retinal cells. In this respect, VEGFR-2, IGF-1, and IGF-1R were localized to Mu¨ller cells.
CONCLUSIONS. These results suggest that sst2 may be protective against angiogenesis. The immediate clinical importance lies in the establishment of a potential pharmacological target based on sst2 pharmacology.
Description: L'articolo è disponibile sul sito dell'editore http://www.arvo.org/eweb/StartPage.aspx?Site=arvo2Sun, 31 Dec 2006 23:00:00 GMThttp://hdl.handle.net/2067/14832006-12-31T23:00:00ZInvolvement of the cAMP-dependent pathway in the reduction of epileptiform bursting caused by somatostatin in the mouse hippocampushttp://hdl.handle.net/2067/1485
Title: Involvement of the cAMP-dependent pathway in the reduction of epileptiform bursting caused by somatostatin in the mouse hippocampus
Authors: Ristori, Chiara; Cammalleri, Maurizio; Martini, Davide; Pavan, Barbara; Liu, Yanqiang; Casini, Giovanni; Dal Monte, Massimo; Bagnoli, Paola
Abstract: The cAMP pathway is major signal transduction system involved in hippocampal neurotransmission. Recently, the peptide somatostatin-14 (SRIF) has emerged as a key signal that, by activating its receptors, inhibits epileptiform bursting in the mouse hippocampus. Little is known on transduction mechanisms which may mediate SRIF function in native cell/tissues. Using a well established model of epileptiform activity induced by Mg2+-free medium with 4-aminopyridine (0 Mg2+⁄4-AP) in mouse hippocampal slices, we demonstrated that PKA-related signaling is upregulated by hippocampal bursting and that treatment with SRIF normalizes this upregulation. We also demonstrated that the SRIF-induced inhibition of PKA impairs phosphorylation of the NMDA receptor subunit NR1. Extracellular recordings of the 0 Mg2+⁄4-AP-induced hippocampal discharge from the CA3 region demonstrated that treating slices with compounds which interfere with PKA activity prevent SRIF inhibition of epileptiform bursting. Our results suggest that SRIF modulation of hippocampal activity may involve PKA-related signaling.
Description: L'articolo è disponibile sul sito dell'editore http://www.springerlink.comMon, 31 Dec 2007 23:00:00 GMThttp://hdl.handle.net/2067/14852007-12-31T23:00:00ZBinding and functional properties of the novel somatostatin analogue KE 108 at native mouse somatostatin receptorshttp://hdl.handle.net/2067/1456
Title: Binding and functional properties of the novel somatostatin analogue KE 108 at native mouse somatostatin receptors
Authors: Cervia, Davide; Langenegger, Daniel; Schuepbach, Edi; Cammalleri, Maurizio; Schoeffter, Philippe; Schmid, Herbert A.; Bagnoli, Paola; Hoyer, Daniel
Abstract: Clinically used somatostatin (SRIF) analogs octreotide and lanreotide act primarily by binding to SRIF receptor subtype 2 (sst2). In contrast, the recently described multiligand SOM230 binds with high affinity to sst1-3 and sst5 and KE 108 is characterised as a high affinity ligand for all five SRIF receptors. In tumoural mouse corticotrophs (AtT-20 cells) and in mouse hippocampus, binding and functional features of KE 108 were examined and compared to SRIF-14, octreotide and SOM230.
In AtT-20 cells, KE 108 bound with high affinity at [125I]LTT-SRIF-28-labelled sites similarly to SRIF, octreotide and SOM230. At the functional level, all four ligands increased guanosine-5’--(3-35Sthio)-triphosphate binding and decreased cAMP accumulation or intracellular Ca2+ concentration through Gi/o proteins. In hippocampal slices, KE 108, octreotide and SOM230 also bound with high affinity at [125I]LTT-SRIF-28-labelled sites similarly to SRIF, but KE108, octreotide or SOM230 did not influence spontaneous epileptiform activity which was, in contrast, inhibited by SRIF.
In conclusion, this study demonstrates that KE 108 has high affinity for native mouse SRIF receptors. Functionally, KE 108 mediates SRIF action at sst2/5 in corticotrophs whereas it does not mimic the SRIF-induced inhibition of hippocampal excitation suggesting that the high potency and efficacy of a synthetic ligand to all known SRIF receptors may not reproduce entirely the effects of the natural SRIF.
Description: L'articolo è disponibile sul sito dell'editore http://www.sciencedirect.com/Fri, 31 Dec 2004 23:00:00 GMThttp://hdl.handle.net/2067/14562004-12-31T23:00:00ZCompensatory changes in the hippocampus of
somatostatin knockout mice: upregulation of somatostatin receptor 2 and its function in the control of bursting activity and synaptic transmissionhttp://hdl.handle.net/2067/1460
Title: Compensatory changes in the hippocampus of
somatostatin knockout mice: upregulation of somatostatin receptor 2 and its function in the control of bursting activity and synaptic transmission
Authors: Cammalleri, Maurizio; Cervia, Davide; Dal Monte, Massimo; Martini, Davide; Langenegger, Daniel; Fehlmann, Dominique; Feuerbach, Dominik; Pavan, Barbara; Hoyer, Daniel; Bagnoli, Paola
Abstract: Somatostatin-14 (SRIF) colocalizes with GABA in the hippocampus and regulates neuronal excitability. A role of SRIF in the control of seizures has been proposed although its exact contribution requires some clarification. In particular, SRIF knock out (KO) mice do not exhibit spontaneous seizures, indicating that compensatory changes may occur in KO. In the KO hippocampus, we examined whether specific SRIF receptors and/or the cognate peptide cortistatin-14 (CST) compensate for SRIF’s absence. We found increased levels of both sst2 receptors (sst2) and CST and we explored the functional consequences of sst2 compensation on bursting activity and synaptic responses in hippocampal slices. Bursting was decreased by SRIF in wild type (WT) mice, but it was not affected by either CST or sst2 agonist and antagonist. sst4 agonist increased bursting frequency in either WT or KO. In WT, but not in KO, its effects were blocked by agonizing or antagonizing sst2, suggesting that sst2 and sst4 are functionally coupled in the WT hippocampus. Bursting was reduced in KO as compared to WT and was increased upon application of sst2 antagonist while SRIF, CST and sst2 agonist had no effect. At the synaptic level, we observed that in WT, SRIF decreased excitatory postsynaptic potentials which were, in contrast, increased by sst2 antagonist in KO. We conclude that sst2 compensates for SRIF absence and that its upregulation is responsible for reduced bursting and decreased excitatory transmission in KO mice. We suggest that a critical density of sst2 is needed to control hippocampal activity.
Description: L'articolo è disponibile sul sito dell'editore http://onlinelibrary.wiley.com/Sat, 31 Dec 2005 23:00:00 GMThttp://hdl.handle.net/2067/14602005-12-31T23:00:00ZSomatostatin receptors differentially affect spontaneous epileptiform activity in mouse hippocampal sliceshttp://hdl.handle.net/2067/1455
Title: Somatostatin receptors differentially affect spontaneous epileptiform activity in mouse hippocampal slices
Authors: Cammalleri, Maurizio; Cervia, Davide; Langenegger, Daniel; Liu, Yanqiang; Dal Monte, Massimo; Hoyer, Daniel; Bagnoli, Paola
Abstract: Somatostatin-14 (SRIF) reduces hippocampal epileptiform activity but the contribution of its specific receptors (sst1-5) is poorly understood. We have focused on sst1 and sst2 role in mediating SRIF modulation of epilepsy using hippocampal slices of wild type (WT) and sst1 or sst2 knock out (KO) mice. Recordings of epileptiform discharge induced by Mg2+-free medium with 4-aminopyridine were performed from the CA3 region before and after the application of SRIF compounds. In WT mice, SRIF and the sst1 agonist CH-275 reduce epilepsy whereas sst1 blockade with its antagonist SRA-880 increases bursting discharge. Activation of sst2 does not affect bursting frequency unless its agonist octreotide is applied with SRA-880, indicating that sst1 masks sst2-mediated modulation of epilepsy. In sst1 KO mice: i. bursting frequency is lower than in WT; ii. SRIF, CH-275 and SRA-880 are ineffective on epilepsy; iii. octreotide is also devoid of effects, whereas blockade of sst2 with the antagonist D-Tyr8 Cyn 154806 increases bursting frequency. In sst2 KO mice, SRIF ligand effects are similar to those in WT. In the whole hippocampus of sst1 KO mice, sst2 mRNA, protein and binding are higher than in WT and RT-PCR of the CA3 subarea confirms an increase of the sst2 messenger. We conclude that sst1 mediates inhibitory actions of SRIF and that interactions between sst1 and sst2 may prevent sst2 modulation of epilepsy. We suggest that, in sst1 KO mice, activation of over-expressed sst2 reduces bursting frequency, indicating that sst2 density represents the rate-limiting factor for sst2-mediated modulation of epilepsy.
Description: L'articolo è disponibile sul sito dell'editore http://onlinelibrary.wiley.com/Wed, 31 Dec 2003 23:00:00 GMThttp://hdl.handle.net/2067/14552003-12-31T23:00:00ZFunctional effect of somatostatin receptor 1 activation on synaptic transmission in the mouse hyppocampushttp://hdl.handle.net/2067/1845
Title: Functional effect of somatostatin receptor 1 activation on synaptic transmission in the mouse hyppocampus
Authors: Cammalleri, Maurizio; Martini, Davide; Timperio, Anna Maria; Bagnoli, Paola
Abstract: Somatostatin-14 (SRIF) co-localizes with GABA in the hippocampus
and regulates neuronal excitability. A role of SRIF
in the control of hippocampal activity has been proposed,
although the exact contribution of each SRIF receptor (sst1–
sst5) in mediating SRIF action requires some clarification. We
used hippocampal slices of wild-type and sst1 knockout (KO)
mice and selective pharmacological tools to provide conclusive
evidence for a role of sst1 in mediating SRIF inhibition of
synaptic transmission. With single- and double-label immunohistochemistry,
we determined the distribution of sst1 in
hippocampal slices and we quantified sst1 colocalization with
SRIF. With electrophysiology, we found that sst1 activation
with CH-275 inhibited both the NMDA- and the a-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated
responses. Results from sst1 KO slices confirmed the
specificity of CH-275 effects; sst1 activation did not affect the
inhibitory transmission which was in contrast increased by sst4
activation with L-803,087 in both wild-type and sst1 KO
slices. The AMPA-mediated responses were increased by
L-803,087. Functional interaction between sst1 and sst4 is
suggested by the finding that their combined activation prevented
the CH-275-induced inhibition of AMPA transmission.
The involvement of pre-synaptic mechanisms in mediating
inhibitory effects of sst1 on excitatory transmission was
demonstrated by the finding that CH-275 (i) increased the
paired-pulse facilitation ratio, (ii) did not influence the AMPA
depolarization in the presence of tetrodotoxin, and (iii) inhibited
glutamate release induced by epileptiform treatment. We
conclude that SRIF control of excitatory transmission through
an action at sst1 may represent an important contribution to
the regulation of hippocampal activity.
Description: L'articolo è disponibile sul sito dell'editore http://onlinelibrary.wiley.com/Wed, 31 Dec 2008 23:00:00 GMThttp://hdl.handle.net/2067/18452008-12-31T23:00:00Z